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Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons

Award Number: R01AA026601
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons - Project Summary Prenatal ethanol exposure (PE) causes fetal alcohol spectrum disorders (FASD), which is characterized by severe cognitive, motor deficits and mood disorders including, major anxiety disorder. FASD affects up to 5% of children and exerts a devastating burden on families, individuals and costs to the society making it one of the most significant health problems in the USA and worldwide. Currently, effective treatments of FASD are limited, which underscores the need for a better understanding of the neuronal mechanisms underpinning the behavioral deficits associated with FASD. Research conducted over the last decades has established that PE impairs the development and function of serotonin (5-HT) system. Although it is widely recognized that dysfunctions of the serotonin (5-HT) system play a major role in depression and major anxiety disorders associated with FASD, the mechanisms by which PE alters the function of dorsal raphe (DRn) 5-HT neurons and the precise 5-HT networks affected remain unknown. To address these important knowledge gaps, we have examined the impact of PE on the function of dorsal raphe (DRn) 5-HT neurons. The results of these studies have established that PE, which induces anxiety phenotype, profoundly, increases the activity of DRn 5-HT neurons, via a persistent potentiation of glutamatergic transmission in the DRn. Importantly, a novel finding of our preliminary mechanistic studies is that these effects are mediated by enhanced nitric oxide (NO) signaling. In this application, we will build on this progress and test the novel hypothesis that enhanced nitrergic function in PE rats mediates the potentiation of glutamatergic transmission onto DRn 5-HT neurons, identify the subset(s) of 5-HT projecting neurons affected, and dissect the neuronal networks mediating anxiety phenotype of PE rats. In Aim 1, we will test the hypothesis that enhanced NO signaling mediates the potentiation of glutamate synapses in the DRn, and identify the subset(s) of DRn 5-HT projecting neurons affected. In Aim 2, we will dissect the glutamatergic input(s) to DRn 5-HT neurons altered in PE rats. In Aim 3, we will test whether reducing specific glutamatergic inputs to DRn 5-HT neurons alleviates anxiety in PE rats. This multidisciplinary approach will identify the cellular mechanisms mediating the dysfunction of 5-HT system and define the neuronal circuitries underlying anxiety phenotype of PE rats. The outcome of these experiments will also lay the foundation for future studies aiming at developing effective therapy of mood disorders associated with FASD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$815 )
2026	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	5	12/4/2025	NON-COMPETING CONTINUATION	-$815
														Subtotal = -$815

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	5	9/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $358,875 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	5	8/19/2022	NON-COMPETING CONTINUATION	$358,875
														Subtotal = $358,875

Issue Date FY: 2021 ( Subtotal = $358,875 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	4	8/16/2021	NON-COMPETING CONTINUATION	$358,875
														Subtotal = $358,875

Issue Date FY: 2020 ( Subtotal = $358,875 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	3	8/4/2020	NON-COMPETING CONTINUATION	$358,875
														Subtotal = $358,875

Issue Date FY: 2019 ( Subtotal = $358,875 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	2	8/7/2019	NON-COMPETING CONTINUATION	$358,875
														Subtotal = $358,875

Issue Date FY: 2018 ( Subtotal = $358,875 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Alcohol Research Programs	000	1	9/17/2018	NEW	$358,875
														Subtotal = $358,875

Grand Total All Awards = $1,793,560

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Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons

Award Number: R01AA026601

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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